Hepatitis C infection is a major worldwide health problem, infection 3-4 million people in the USA alone. The long-term sequelae of infection include chronic hepatitis, cirrhosis, and hepatocellular carcinoma. One reason for the scale of these complications is that approximately 70% of acute infections lead to chronicity. In order to develop an effective vaccine it will be critical to understand the factors that lead to resolution of infection. It is thought that the failure of the immune system to clear infection the majority of the time is due to the extreme is thought that the failure of the immune system to clear infection the majority of the time is due to the extreme mutability of the virus RNA genome. In a manner similar to HIV-1, this virus exists as a mixture of related sequences termed quasispecies that are able to rapidly evolve under immune selection pressure and hereby escape host immune defenses. Although the nature of the immune responses that correlate with clearance remain elusive, it appears that vigorous broadly directed helper and cytotoxic T lymphocyte (CTL) responses favor resolution. The Chimpanzee model offers a unique opportunity to perform a detailed immunologic analysis of natural infection. The goal of this program project is to simultaneously evaluate HCV-specific immune responses and quasispecies evolution over the course of acute HCV infection. Carefully designed T cell subset depletion experiments will determine the immune responses that control viral replication and the impact they have on viral evolution. Project 2 will evaluate the T cell receptor repertoire of these immune responses, and apply powerful molecular techniques to longitudinally track the persistence of HCV-specific T cell clones in liver and peripheral blood of infected animals. We will also track the prevalence of TCR transcripts through the depletion of recovery phase of T cells over the course of acute and chronic infection. These experiments will provide a clearer picture of the role of cell-mediated immune responses in the control of HCV replication.